Obstructive sleep apnea (OSA) is a disorder characterized by recurrent collapse of the upper airway during sleep. The ultimate cause of OSA is widely believed to be an anatomically small pharyngeal airway. Smaller oropharyngeal passages have increased resistance compared to normals, which results in increased negative pressures generated during inspiration. These conditions do not result in airway collapse during waking because reflex activation of airway dilator muscles in response to negative pressure (the negative pressure reflex; NPR) maintains airway patency. However, the NPR is diminished at the transition from wake to sleep, and reversed during REM sleep, with consequential loss of muscle activation and airway collapse in susceptible individuals. In contrast, this state-dependence decline in NPR has little consequence to normal individuals because they are not dependent upon it to keep their airways patenL Thus a rational therapeutic goal for OSA is to identify a means to attenuate or prevent decreases in the NPR during sleep. Unfortunately little is known of the central pathways that mediate the NPR and consequently little of the mechanisms of state dependence of this reflex. In animal models the afferent signal is carried by the superior laryngeal branch of the vagus nerve (sin), which terminates in the interstitial subnucleus of the nucleus of the solitary tract (NTSis). In both animals and humans the genioglossus (gg), the primary protruder muscle of the tongue, is one of the muscles activated by this reflex. It is unknown whether neurons in the NTSis project directly to the hypoglossal motoneurons that innervate the gg (ggHMNs) or information is relayed via premotoneurons. If the latter, it is important to locate these neurons as they may be key substrates for sleep-state modulation of the NPR. The Specific Aims of this project are designed to address these gaps in our knowledge. We intend to discover first, the brain regions that convey negative pressure afferent signals to the upper airway musculature; second, the neurotransmitters that could mediate the statedependent decline in the NPR with an ultimate long term goal of discovering a systemic pharmacological intervention to ameliorate state-dependent decrements in upper airway patency.